N, beta-disubstituted and phenethyl piperidines



United States Patent This invention relates to new chemical compoundswhich possess useful physiological properties and to a process for thepreparation of these compounds.

The new compounds of the present invention may be regarded as basicether derivatives of N-,/3-disubstitutedu-phenethylamines. They may berepresented by the R IYIH formula:

in which the group represented by R is a basic ether group of theformula O(CH Arn, in which Am is a dialkylaminoor amonocyclic-nitrogen-containing heterocyclic group joined to the'alkylchain through a nitrogen atom. The dialkylamino groups contain alkylgroups of from one to four carbon atoms, while the monocyclicheterocyclic groups include the morpholino, piperidine, and .pyrrolidinogroups. n is an integer from two to four. One of the radicals X and Yrepresents a heterocyclic radical and the other an aryl or substitutedaryl.

Typical of the aryl groups that X or Y may represent are phenyl,chlorophenyl, bromophenyl, iodophenyl, fluorophenyl,trifluoromethylphenyl, tolyl, and methoxyphenyl. Typical heterocycliegroups that X or Y may represent are pyridyl, piperidyl and N-loweralkyl piperidyl.

This invention also includes nontoxic acid addition salts and quaternarysalts of the compounds of the general formula.

The compounds of this invention may be prepared in several ways inaccordance with the individual struc tural requirements. TheN,fl-disubstituted-a-phenethylamines may be prepared by the reaction ofa suitable organometallic derivative- 0f X or Y with an anilsubstit-uted with the O(CH Am group. The anil is obtained by thereactionof a basic-ether substituted benzaldehyde with an aminederivative of X or Y.

Illustrations of preparative methods are schematically represented asfollows:

xylene H2 0 ice Compounds of Type I may be catalytically hydrogenated togive the piperidine derivatives, (II):

The N-alkyl piperidine derivatives may be prepared in the followingmanner:

By substituting other acid chlorides in the above re action, as forexample, propionyl chloride, butyryl chloride, etc., the N-propionyl andN-butyryl derivatives are obtained, which on reduction with LiAlH giverise to the corresponding N-propyl and N-butyl derivatives.

The reaction of an organometallic with the anils of our invention isusually carried out at room temperature or slightly above in ananhydrous ether solvent. However, these reactions are operative atsomewhat lower temperatures, for example to 20 C. and also at highertemperatures to about 150 C. These temperatures may be achieved bycooling the reaction mixture, or by use of a higher boiling solvent suchas tetrahydrofuran (B.P. 65 to 66 C.) or di-n-butylether (B.P. 142 C.).Another method generally used to achieve higher reaction temperatures isthe preparation of the organometallic in the usual manner in diethylether and then replacing the ether with a hydrocarbon solvent such asbenzene (B.P. 80 C.) or toluene (B.P. 110 C.) for the subsequentreaction of the organometallic reagent with the anil. The reaction timehere is not critical and at the preferred temperatures the reaction isordinarily complete in a short period, i.e., thirty minutes to twohours. For these reactions preferred procedure involves the use ofsubstantially equimolar quantities of the reactants, however a to excessof the organometallic is commonly used.

After the reaction is completed the reaction mixture is decomposed bypouring onto ice, water, or a saturated ammonium chloride solution. Theorganic layer is separated, washed with water, and dried. Upon removalof the solvent the product may be isolated generally as yellowish highlyviscous oils, some of which may crystallize. Purification is effected bydistillation or chromatography on alumina.

The anils, i.e., the product of the reaction of anappropriately-substituted benzaldehyde with an appropriately-substitutedaniline may be prepared by a variety of methods. For example, reactionmay be conveniently effected by bringing the reactants together in anon-reactive solvent such as alcohol, n-heptane, benzene, toluene, orxylene. Elevated temperatures such as the reflux temperature are.generally employed to increase the reaction rate. As the reactionproceeds, water is formed, and in hydrocarbon solvents the water may beazeotropically removed and collected in a trap. After the theoreticalamount of water is collected the reaction is considered completed. Thismay require from two to forty-eight hours. Anil formation may also beeffected merely by mixing the reactants at elevated temperature, i.e.,at temperatures above room temperature. Preferably, the reaction iscarried out at temperatures in the range from about 80 to 150 C. Thereaction time here is not critical and at the preferred temperatures thereaction is ordinarily complete in a short period, i.e., minutes to twohours. The proportion of the reactants is not critical, however apreferred procedure involves the use of substantially equimolarquantities of the reactants. The products may be purified bydistillation, or by column chromatography on alumina.

The compounds of the present invention are potent inhibitors ofcholesterol biosynthesis. These compounds appear to work by a differentmechanism than triparanol and other related basic ether substitutedtriphenylethanols by inhibiting cholesterol synthesis at a differentstage in the biosynthetic pathway. These compounds are, therefore,useful in reducing the total sterol content in blood and tissues.

The compounds are active when administered by the oral route and may begiven in any conventional dosage form such as capsule, tablet,suspension or the like in amounts ranging from 10 mgs. to one gram perday.

One hundred ml. of an ether solution containing 29 g.

(0.09 mole) of N-[p-(p-diethylaminoethoxy)-benzyland 60 pounds ofhydrogen pressure.

idine]-p-chloroaniline was added with stirring to 0.14 mole of2-picolyllithium in ml. of ether. Addition was carried out at a ratesufl'icient to maintain a gentle refluxing of the ether. The mixture wasrefluxed for 30 minutes and then the complex was decomposed with anaqueous solution of ammonium chloride. The organic layer was removed anddried over anhydrous sodium sulfate. The ether was removed at reducedpressure and the unreacted 2-picoline distilled off by heating the darkresidue at C. at 1 mm. of Hg pressure. The residue was crystallized frompetroleum ether to give 24.7 g. of 2-{2-(p-chloroanilino -2 p-B-diethylaminocthoxy phenyl]ethyl}pyri-dine, melting at 76 to 77 C.

The N- [p-( p-diethylaminoethoxy) benzylidine] -p-chloroaniline wasprepared as follows:

A mixture of 20 g. (0.0945 mole) of p-(B-diethylaminoethoxy)benzaldehydeand 12.1 g. (0.0945 mole) of p-chloroaniline were heated in 25 ml. ofrefluxing 95% ethanol for 2 hours. The ethanol was removed and theresidue was heated on an oil bath to 240/0.5 mm. to remove unreactedstarting material. Upon cooling, the residue solidified to give 29.8 g.of brownish yellow product. Recrystallization from petroleum ether gavea nearly-white solid, melting at 38 to 40 C.

Example II.2 {2 (p chloroanilino)-2-[p-(B-diethylaminoethoxy phenylethyl} pi peridine An acetic acid solution of 2-{2-(p-chloroanilino)-2-[p-(,B-diethylaminoethoxy)phenyl] ethyl}pyridine was hydrogenated, using0.2 g. of platinum oxide as catalyst After the theoretical amount ofhydrogen was absorbed, the catalyst was removed by filtration, thesolvent evaporated and the acid salt neutralized. The desired product,2-{2- (p chloranilino) -2-'[p- (B-diethylaminoethoxy) phenyl]ethyl}piperidine was obtained as an oil, boiling at 144 C. at 0.2 mm.pressure.

Example IlI.-2 {2 (p toluidino) Z-[p-(fl-diethylaminoethoxy) phenyl]ethyl}pyridine The reaction of p-(B-diethylaminoethoxy)-benzaldehyde andp-toluidine by the procedure of Example I gave the desired anil,N-[p-(,B-diethylaminoethoxy)benzylidine]-p-toluidine, as an oil, whichwas used without further purification. When this anil was used in placeof the anil of Example I,2-{2-(p-toluidino)-2-[p-(;3-diethylaminoethoxy)phenyl]ethyl}-pyridinewas obtained. The product, purified by chromatography on alumina, wasobtained as a white solid melting at 77 to 79 C.

ExampleIV.2{2-(-t0luidin0)-2-[p-(;8-diethylaminoethoxy)phenyl]ethyl}piperidin'eThe product of Example III, 2-{2-(p-toluidino)-2-[p-(fi-diethylaminoethoxy)phenyl]-ethyl}pyridine, was hydrogenated by theprocedure of Example II to give the desired 2-{2- (p-tolu idino -2- [p-(fi-diethylaminoethoxy phenyl]ethyl}pipen'dine as a white solid, meltingat 785 to 79.5 C.

Example V.-2-{2-anilino-2- [p- (fl-dietylaminoethoxy phenyl ethyl}pyridine The reaction of p-(B-diethylaminoe-thoxy)-benzaldehyde andaniline by the procedure of Example I gave the desired anil,N-[p-(fi-diethylaminoethoxy)benzylidene]- aniline as an oil. When thisanil was used in place of the anil of Example 1,2-{2-(p-anilino)*2-[p-(B-diethylaminoethoxy)phenyl]ethyl}pyridine wasobtained as a white solid melting at 61 to 63 C.

Example VI .--2-{2- (m-chloroanilino) -2- p- B-diethylaminoethoxy phenylethyl} pyridine The reaction of p-(fi-diethylaminoethoxy)benzaldehydeand m-chloroaniline by the procedure of Example I gave the desired anil,N- [p-(B-diethylaminoethoxy)benzylidenel-m-chloroaniline, obtained as anoil. When this anil 5 was used in place of the anil of Example I,2-{2-(m-chloroanilino) 2 [p-(B-diethylaminoethoxy)phenyl]ethyl} pyridinewas obtained as a nearly white solid, melting at 62 to 64 C.

amineth0xy)phenyl ethyl} pyridine The reaction ofp-(B-diethylaminoethoxy) benZaldehyde and p-methoxyaniline by theprocedure of Example I gave the desiredN-[p-(B-diethylarninoethoxy)benzylideneJ-p-methoxyaniline, whichcrystallized from petroleum ether as a white solid, melting at 66 to 67C. When this anil was used in place of the anil of Example I, 2-{2- (pmethoxyanilino)-2-[p-(p-diethylaminoethoxy)phenyl]ethyl}pyridine wasobtained, melting at 66 to 68 C.

The reaction of p-(B-diethylaminoethoxy) benzaldehyde andp-fluoroaniline by the procedure of Example I gave the desired anil,N-[p-([i-diethylaminoethoxy)benzylidene]-p-fluoroaniline as an oil, B.P. 182 C./ 0.09 mm. When this anil replaced the anil of Example I,2-{2-(pfluoroanilino) 2 [p-(fl-diethylaminoethoxy)phenyl] ethyl}pyridinewas obtained, melting at 53 to 56 C.

Example IX .2-{Z- p-tolaidino -2- [p-( ,B-piperidinoethoxy -phenylethyl} pyridine The reaction of p-(fl-piperidinoethoxy)benzaldehyde andp-toluidine by the procedure of Example I gave the desired N[p-(fl-piperidinoethoxy)benzylidene1-p-toluidene which crystallized frompetroleum ether as a solid, melting at 70 to 72 C. When this anil wasused in place of the anil of Example I, 2-{2-(p-toluidino)-2-[p-(5-piperidinoethoxy)phenyl] ethyl}pyridine was obtained, melting at 95to 97 C.

Example X .--2-{2 (p-toluidino) -2- [p-( B-morpholinoethoxy )phenyl]ethyl}pyridine The reaction of p-(jS-morpholinoethoxy)benzaldehyde andp-toluidine 'by the procedure of Example I gave the desiredN-[p-({B-morpholinoethoxy)benzylidene]-p-toluidine, which crystallizedfrom petroleum ether as a solid melting at 110 to 112 C. When this anilwas used in place of the anil of Example I, 2-{2-(p-toluidino)-2-[p- 3morpholinoethoxy)phenyl]ethyl}pyridine was obtained, melting at 103 to105 C.

The reaction of p-(,B-pyrrolidinoethoxy)benzaldehyde and p-anisidine bythe procedure of Example I gave the desired N- [p-,B-pyrrol-idinoethoxy) benzylidene] -p-anisidine as a solid, melting at85 to 87 C. When this anil was used in place of the anil of Example I,2-{2-(p-anisidino) 2-[p-(fl-pyrrolidinoethoxy)phenyl]ethyl}pyridine wasobtained, melting at 93 to 95 C.

The product of Example X, 2-{2-(p-toluidino)-2-[p-(p-morpholinoethoxy)phenyl]ethyl}pyridine, was hydrogenated by theprocedure of Example II to give '2-{:2(ptoluid-ino)2-[p-(fl-mopholinoethoxy)phenyl]ethyl}piperidine which did notcrystallize and was isolated as a pale amber, viscous oil bychromatography on alumina.

Example XIlI.-2-{2-(m-trifluor0methylanilino)-2- [p-.(,B-diethylaminoethoxy)phenyl] etlzyl}pyridine The reaction ofp-(B-diethylaminoethoxy)benzaldehyde and m-trifluoromethylaniline by theprocedure of Example I gave the desired N- [p-(B-diethylaminoethoxy)benzylidene]-m-trifiuoromethylaniline as an oil. When this anil was usedin place of the anil of Example I, 2-{2-(m-trifluoromethylanilino)Z-Ip-(B-diethylaminoethoxy)phenyl]ethyl}pyridine was obtained as a paleyellow, viscous oil, which was purified by chromatography on an aluminacolumn.

The reaction of m-(fl-diethylaminoethoxy)benzaldehyde andp-chloroaniline by the procedure of Example I gave the desired.-N-[-m-(B-diethylaminoethoxy)benzylidine]-p-chloroaniline as an oil,B.P. 215 C. at 0.3 .mm. When this anil was used in place of the anil ofExample I, 2 {2 (p-chloroanilino') 2 [m-(fl-diethylaminoethoxy)phenyl]ethyl}pyridine was obtained as an oil, B.P. 207 to 209 Cpat 0.08mm.

. Example XV.-2-{2-(p-chloroanilino -2- [12 ('y-t limethylam inopropoxyphenyl ethyl} pyridine The reaction ofp-('y-dimethylaminopropoxy)benzaldehyde and p-chloroaniline by theprocedure of Example I gave the desired N-[p-(y-dimethylaminopropoxy)benzylideneJ-p-chloroaniline as a solid, meltingat 62 to 64 C. When this anil was used in place of the anil of ExampleI, 2-{2- (p-chloroanilino -2- [p- -dirnethylaminopropoxy)phenyl]ethyl}pyridine was obtained.

Example X VI .-2-{2-anilin0-2- [p-(y-piperidinopropoxy)phenyl]ethyl}pyridine The reaction ofp-(w-piperidinopropoxy)benzaldehyde and aniline by the procedure ofExample I gave the desired N-[p-(wpiperidinopropoxy)benzylidene]anilineas a solid, melting at 495 to 50.5 C. When this anil was used in placeof the anil of Example I, 2-{2-anilino-2-[p-('y-piperidinopropoxy)phenyl]ethyl}pyridine was obtained, melting at88 to 91 C.

Example XVII.-2-{a- [p-(B-diethylaminoelhoxy)phenyl]-fi-phenylethylamino}pyridine The reaction ofp-(fi-diethylaminoethoxy)benzaldehyde and 2-aminopyridine gave thedesired anil, N-[p-(fI-diethylaminoethoxy)benzylidene]-2-pyridylamine.When this anil was allowed to react with an ether solution of benzylmagnesium chloride as in the procedure of Example I, there was obtained2-{a-[p-(B-diethylaminoethoxy)phenyl]- 3-phenylethylamino}pyridine,melting at 75 to 76 C.

Example XVIII.4-{2-(p-chloroanilino) -2- [p-(fi-a iethylaminoethoxy)phenyl] ethyl}pyridine When 4-picolyl lithium replaced 2-picolyl lithiumin Example I, there was obtained 4-{2-(p-chloroanilino)-2- [p 3diethylaminoethoxy)phenyl]ethyl}pyridine as a light amber, viscous oil,which was purified by chromatography on an alumina column.

Example XIX.--2-{2- [p-(B-diethylaminoethoxy)phenyl]Z-(p-toluidino)ethyl}-1-ethylpiperidine wherein R is a member selectedfrom the group consisting of H and lower alkyl, X is a member selectedfrom the group consisting of phenyl, halopheny l, trifiuoromethylphenyl,loweralkylphenyl and loweralkoxyphenyl; n is an integer from 2 to 4; andAm is a member selected from the group consisting of diloweralkylamino,morpholino, piperidino and pyrolidino, the nitrogen atoms of said groupsbeing attached to the --(CH group.

2. 2-{2-(p-toluidino)-2-[p-(fi-morpholinoethoxy)phenyl]ethyl}piperidine.

3. 2-{2-[p-(B-diethylaminoethoxy)phenyl] 2-(p-toluidino)ethyl}-1-ethylpiperidine.

4. 2-{2-(p-chlor0anilino)-2-[p-(fl-diethylaminoethoxy) phenylethyl}piperidine.

5. 2-{2-(p-toluidino) 2 [p-(fl-diethylaminoethoxy) phenyl] ethyl}piperidine.

References Cited by the Examiner UNITED STATES PATENTS 2,971,001 2/1961Palopoli et al 260294.7 3,075,971 1/1963 Bencze 260296 X 3,097,2077/1963 Maddox et al 260294.7

OTHER REFERENCES 15 WALTER A. MODANCE, Primary Examiner.

DUVAL T. MCCUTCHEN, NICHOLA S. RIZZO, JOHN D. RANDOLPH, Examiners.

1. A COMPOUND OF THE FORMULA: